A human supergene: BRCA1 and U2 snRNAs

Background and Objectives BRCA1 resides on one of two major haplotypes in populations of European and Asian ancestry, with greater haplotypic diversity in populations of African ancestry. Near-maximal linkage disequilibrium associated with these haplotypes extends for more than 300 kilobases from RND2 to RNU2. We undertook to characterize the region of suppressed recombination and understand the evolutionary history of its haplotypes. Methodology We analysed phased variants from the 1000 Genomes Project together with ancient and archaic hominin sequences. We characterized linkage disequilibrium, haplotype relationships (principal-components analysis, genealogies), and neutrality statistics, and examined the genomic architecture of the region on the CHM13 and GRCh38 assemblies. Results Two major haplogroups, inherited as if alleles at a single locus, are present in all populations, while a third is common in Africa. Sequences predicted to form strong secondary structures lie near the boundaries and are proposed to suppress recombination through replicative stress and interference with meiotic synapsis. The haplotypes differ in expression and reproductive phenotypes, and show characteristics consistent with an old balanced polymorphism. Conclusions and Implications The RND2–RNU2 region meets criteria to be considered a supergene. The long-range linkage disequilibrium within the region should be considered when identifying pathogenic BRCA1 mutations in families with hereditary breast and ovarian cancer.